Complement fixation by immune complexes is the crucial link between the immunoglobulin recognition system and the complement effector system of human serum. Activation of the complement cascade by antigen--immunoglobulin G complexes involves a specific interaction between the CH2 domain of the antibody heavy chain and the globular head of the Clq complement component. This interaction induces activation of Cl through selective proteolysis of Clr and Cls. The subsequent steps in the complement cascade result in stimulation of inflammation, cell opsonization, and cell killing. We have prepared synthetic peptides from the CH2 domain of IgGl that both bind to Cl and inhibit the binding of IgGl to Cl. A hydrophobic pentapeptide containing tryptophan-277 and a basic decapeptide containing histidine-285 were each active and a 16-residue peptide containing both residues was even more active. Thus the binding site of IgGl contains both a hydrophobic region and an ionic region. This project will explore the antibody-binding site of Clq by identifying the structural features of the CH2 site that facilitate binding. A series of radiolabeled peptides will be prepared by solid-phase peptide synthesis that define the roles of tryptophan-277 and histidine-285 in enhancing complement fixation. These synthetic peptides will themselves be antagonists of complement fixation. By dimerization in solution or by attachment to solid supports, these peptides will be converted into synthetic agonists that directly fix complement. In addition, analogues of these peptides will be prepared for covalent affinity labeling and identification of the humoral Clq receptor site for the CH2 domain of IgG.